Gaseous contrast agents and, more specifically, hyperpolarized (HP) noble gases, such as helium-3 (3He) and xenon-129 (129Xe), are used for investigational imaging of respiratory gas in lungs by MRI for the purpose of assessment of regional lung function. The ultimate goals of such imaging methods include diagnosis, evaluation, and monitoring progression of respiratory diseases, as well as evaluating the efficacy of therapeutic interventions. The pulmonary diseases that can benefit from such an imaging modality include obstructive lung diseases (e.g. emphysema, chronic bronchitis, and asthma) and interstitial lung diseases (e.g. cystic fibrosis and idiopathic pulmonary fibrosis).
HP-gas MRI has enabled pulmonary researchers to investigate different aspects of lung function and structure non-invasively and at a localized level. Stable isotopes of noble gases 3He (which, contrary to the natural “balloon” helium, 4He, are visible by MRI) and 129Xe can be polarized through optical pumping with circularly polarized laser light in a machine referred to as a polarizer. They can then be safely inhaled by a human subject lying down inside an MRI scanner (albeit for investigational use only, as this process is not currently approved by the FDA). Images of HP-gas atoms in the airways can then be rapidly acquired by MRI through the direct visualization of respiratory gas distribution in pulmonary airways. The acquirable imaging signal-to-noise ratio (SNR) from HP gases is proportional to their polarization level. The polarization build-up of a HP species is maintained in the polarizer using an external magnetic field (typically a few tens to hundreds of Gauss) and by ensuring a highly clean storage environment (e.g. a baked and evacuated glass cell in the case of 3He or a cryogenic trap in the case of 129Xe). However, the moment HP gas is dispensed from the polarizer, its polarization starts decaying (i.e. relaxes) with a time constant in the order of a few tens of minutes, and therefore it needs to administered and imaged almost immediately. This relaxation rate is even faster in vivo (in the order of a few tens of seconds), primarily due to interactions with other respiratory gas components (most notably the oxygen molecules as discussed further below) and collisions with lung tissue walls.
Generic Applications
Diffusion-weighted HP gas MRI allows for assessing lung microstructure in a similar fashion to CT scans. Single-breath ventilation MRI (also referred to as a spin density map), on the other hand, provides a qualitative picture of respiratory gas distribution in the lungs in a similar fashion to nuclear medicine ventilation scans (e.g., 133Xe SPECT or 13N2 PET). Ventilation scans allow for the detection and qualitative evaluation of gross ventilation defects due to airway obstruction or air trapping. Both of these methods can be performed during a short breath-hold (a few seconds) after inhaling a single-breath bolus of HP gas (either with or without oxygen).
Oxygen Tension Imaging
Recently, more sophisticated imaging methodologies have been developed based on HP gas MRI technology to extract richer and more valuable regional information about lung function. At the same time, they pose certain requirements on the delivery pattern and mixture content of the HP gas during the imaging session. Oxygen-weighted HP gas MRI, which is used to measure regional alveolar partial pressure of oxygen (PAO2), requires real-time mixing of HP 3He with oxygen as closely as possible at the normoxic ratio of 3He:O2≈79:21. It is necessary to maintain the oxygen content in the inspired gaseous contrast agent at a similar level as normal breathing air (Fraction of Inspired Oxygen (FiO2)=0.21) in order to obtain the most physiologically meaningful alveolar oxygen tension (PAO2) measurements. However O2 molecules exhibit strong paramagnetic properties (due to the unpaired spins of their outermost two electrons), which in turn leads to a strong dipolar interaction with noble gas species and subsequently causes rapid depolarization (relaxation) of the HP gas. Excessive depolarization of the HP gas is undesirable because it naturally limits the obtainable signal in MR images and will subsequently have a negative effect on the accuracy of quantitative measurements. The depolarization time constant in the case of 3He is approximately 20 sec under nominal physiological conditions (body temperature, atmospheric pressure and O2 partial pressure of ˜200 mbar). Premature mixing of oxygen and HP noble gas should therefore be avoided if possible. This means that the mixing of the HP gas and oxygen should be performed immediately before the subject inhales the mixture. Since the mixing and inspiration of the mixture may take up to several seconds, there is still a great chance of losing substantial amounts of polarization; up to 30-40% before imaging is performed. It has therefore become customary to keep the HP gas and oxygen components in separate containers (e.g. in specialty plastic bags, divided by the 79:21 volume ratio) separated by a Y-connector and dedicated valves. Immediately before image acquisition, the valves are opened and the subject simultaneously inhales the contents of both bags, thereby minimizing the time that HP gas and oxygen are in contact with each other.
This approach has a major drawback—it does not guarantee that the same proportional amount of HP gas and oxygen is flowing into the lungs throughout the respiratory cycle. For example, the FiO2 can vary substantially (e.g., from 0.10 to 0.30) while depleting the contents of the two bags. Even though the proper amount of gas is stored in each bag, the respiratory effort that the subject applies to the bags and the different tubing resistance between the two flow paths can easily lead to very different flow rates and a varying resulting mixture. This may not initially appear as a major problem, because, given enough time, the subject will eventually inhale the entire contents of both bags before committing a breath-hold for MRI. The non-uniform mixing of the two gases, however, can have a drastic effect on measurements of oxygen tension in the lungs and can drastically skew the PAO2 values, as has been observed experimentally. For example if the HP 3He bag deflates faster than the O2 bag, then the concentration of oxygen in the lung parenchyma of the subject will be lower than normal, whereas the trachea (which was filled later by oxygen) will contain a higher-than-normal oxygen concentration. This induces a non-physiological oxygen gradient in the pulmonary airways, which directly affects the PAO2 values and would be very difficult or impossible to correct for, especially if the flow ratio information is missing. The proposed device largely eliminates this problem by real-time monitoring and control of the two respiratory gas components (i.e. HP gas and oxygen) while maintaining FiO2 and total volume at the desired levels.
Specific Ventilation Imaging
Another recently developed HP gas MRI method is specific ventilation imaging, which is arguably the only HP gas-based quantitative ventilation imaging technique currently available. This is in contrast to single-breath ventilation imaging, which requires qualitative interpretation by an expert reader. Specific ventilation imaging is based on the delivery of a number of identical HP gas breaths to the subject while acquiring an image of HP gas distribution in the lungs during a short end-inspiratory breath-hold. This idea had been implemented in sedated animals in a fairly straightforward fashion by using a programmable mechanical ventilator. In these implementations, the mechanical ventilator takes control of the respiratory pattern in the sedated and intubated animal, delivers the desired quantity of HP gas mixed with oxygen per breath, commits a breath-hold for image acquisition, and repeats this sequence as many times as desired. In the case of consciously breathing humans, however, such a maneuver is not easily justifiable. A human subject needs to be able to comfortably inhale the HP gas and oxygen mixture through a mask or a mouthpiece and hold his or her breath when reaching the target inspired volume, at which point the images are acquired. The subject should then exhale the gas and continue this pattern at a comfortable breathing rate until the image acquisition sequence is completed (typically over 6-8 breaths).
Accordingly, there is a need in the pertinent art for imaging systems and methods that permit real-time mixing of HP gas and oxygen in order to prevent premature depolarization of the contrast gas while maintaining FiO2 at a normoxic level for the subject's safety. There is a further need in the pertinent art for imaging systems and methods that permit control of the delivered tidal volume (VT) at a specific level in order to image the lung at the same inflation volume over the sequence of several breaths, both for physiological stability and for matching images from different breaths; i.e. image co-registration.